A5001798787- Lung Cancer Treatments and Mutations
- HER2/EGFR in Cancer Research
- RNA modifications and cancer
- Colorectal Cancer Treatments and Studies
- Lung Cancer Research Studies
- Cancer therapeutics and mechanisms
- Cancer Mechanisms and Therapy
- Monoclonal and Polyclonal Antibodies Research
- PI3K/AKT/mTOR signaling in cancer
- Radiopharmaceutical Chemistry and Applications
- Cancer Genomics and Diagnostics
- Melanoma and MAPK Pathways
- Cholangiocarcinoma and Gallbladder Cancer Studies
- Cancer Research and Treatments
- Neuroendocrine Tumor Research Advances
- Cytokine Signaling Pathways and Interactions
- Retinoids in leukemia and cellular processes
- Myasthenia Gravis and Thymoma
- Neuroblastoma Research and Treatments
- Veterinary medicine and infectious diseases
- Pancreatic and Hepatic Oncology Research
- Occupational and environmental lung diseases
- Cancer Immunotherapy and Biomarkers
- Ubiquitin and proteasome pathways
- Gastric Cancer Management and Outcomes
Dana-Farber Cancer Institute
2014-2025
Harvard University
2013-2025
Brigham and Women's Hospital
2011-2021
Hyogo Prefectural Amagasaki General Medical Center
2019
Massachusetts General Hospital
2013
Shikoku Cancer Center
2008-2012
Okayama University
2005-2011
Dana-Farber Brigham Cancer Center
2011
Broad Institute
2011
Okayama University Hospital
2006
Anaplastic lymphoma kinase (ALK) tyrosine inhibitors (TKI), including crizotinib, are effective treatments in preclinical models and cancer patients with ALK-translocated cancers. However, their efficacy will ultimately be limited by the development of acquired drug resistance. Here we report two mechanisms ALK TKI resistance identified from a crizotinib-treated non-small cell lung (NSCLC) patient line generated resistant tumor (DFCI076) as well studying version (TAE684)-sensitive H3122...
Abstract Purpose: BRAF mutations are found in a subset of non–small cell lung cancers (NSCLC). We examined the clinical characteristics and treatment outcomes patients with NSCLC harboring mutations. Experimental Design: Using DNA sequencing, we successfully screened 883 for between July 1, 2009 16, 2012. Baseline were compared without Wild-type controls consisted somatic alteration BRAF, KRAS, EGFR, ALK. In vitro studies assessed biologic properties selected non-V600E identified from NSCLC....
Irreversible pyrimidine-based EGFR inhibitors, including WZ4002, selectively inhibit both EGFR-activating and inhibitor-resistant T790M mutations more potently than wild-type EGFR. Although this class of mutant-selective inhibitors is effective clinically in lung cancer patients harboring EGFR(T790M), prior preclinical studies demonstrate that acquired resistance can occur through genomic alterations activate ERK1/2 signaling. Here, we find reactivation occurs rapidly following WZ4002...
Abstract Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are commonly used to treat non-small cell lung cancers with EGFR mutations, but drug resistance often emerges. Intratumor heterogeneity is a known cause of targeted therapy and considered major in treatment failure. This study identifies clones EGFR-mutant tumors expressing low levels both wild-type mutant protein. These EGFR-low cells intrinsically more tolerant inhibitors, invasive, exhibit an...
Abstract The epidermal growth factor receptor (EGFR)–specific tyrosine kinase inhibitor gefitinib may provide dramatic clinical responses in some patients with pulmonary adenocarcinoma carrying activating mutations of the EGFR. However, prolonged administration eventually induce acquired resistance such patients. To gain insight into mechanisms this phenomenon, we placed PC-9, a cell line derived from that has 15-bp deletion EGFR exon 19, under continuous selective pressure low levels...
Insertion mutations in EGFR and HER2 both occur at analogous positions exon 20. Non-small cell lung cancer (NSCLC) patients with tumors harboring these seldom achieve clinical responses to dacomitinib afatinib, two covalent quinazoline-based inhibitors of or HER2, respectively. In this study, we investigated the effects specific 20 insertion from NSCLC that had clinically achieved a partial response after treatment. We identified Gly770 as common feature among drug-sensitive mutations....
Vandetanib is a novel multitarget tyrosine kinase inhibitor (TKI) that inhibits vascular endothelial growth factor receptor-2 (VEGFR-2), with additional inhibition of epidermal receptor (EGFR) and rearranged during transfection signaling, which has shown promising results in clinical trials for advanced non-small cell lung cancer. However, the mechanisms acquired resistance to vandetanib remain unclear. Therefore, we established vitro vandetanib-resistant PC-9/VanR cells from PC-9,...
Patients with pulmonary adenocarcinoma carrying the epidermal growth factor receptor ( EGFR ) mutation tend to display dramatic clinical response treatment tyrosine kinase inhibitor gefitinib. Unfortunately, in many cases cancer cells eventually acquire resistance, and this limits duration of efficacy. To gain insight into these acquired resistance mechanisms, we first prepared HEK293T cell line stably transfected either wild‐type (WT) or mutant (L858R) , then expressed oncogenic K‐Ras 12V...
Abstract RAS gene mutations are the most frequent oncogenic event in lung cancer. They activate multiple RAS-centric signaling networks among them MAPK, PI3K, and RB pathways. Within MAPK pathway, ERK1/2 proteins exert a bottleneck function for transmitting mitogenic signals activating cytoplasmic nuclear targets. In view of disappointing antitumor activity toxicity continuously applied MEK inhibitors patients with KRAS-mutant cancer, research has recently focused on as therapeutic targets...
Small-cell lung cancer (SCLC) occurs infrequently in never/former light smokers. We sought to study this rare clinical subset through next-generation sequencing (NGS) and by characterizing a representative patient-derived model. performed targeted NGS, as well comprehensive pathological evaluation, 11 smokers with clinically diagnosed SCLC. established model from one such patient (DFCI168) harboring an NRASQ61K mutation characterized the sensitivity of MEK TORC1/2 inhibitors. Despite...
A subset of drug-resistant EGFR -mutant MET -amplified lung cancer switches oncogenic dependence to and is treatable with inhibitor monotherapy.
We evaluated the safety and efficacy of gefitinib treatment in elderly patients with non-small-cell lung cancer (NSCLC). retrospectively compared toxicity, response survival outcomes for aged 75 years or older (elderly group) same younger than years. In total, 350 were eligible this analysis, whom 92 group 258 non-elderly group. group, adverse events generally mild to moderate grade 3–4 observed 8 (9%) patients. The objective rate (17 vs. 21% non-elderly, respectively) median time (7.6 9.3...
Abstract Although gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, has been shown a significant activity for recurrent non‐small‐cell lung cancer (NSCLC), its long‐term adverse effect with continuous usage hitherto not clearly elucidated. Subjects were 108 consecutive NSCLC cases who treated gefitinib between November 2001 and December 2004 at our single institution. A crude incidence rate ratio was calculated by of in subject to population‐based incident all...
Helicobacter cinaedi is a rarely encountered pathogen that easily induces bacteremia. Various foci of H. infection have been reported; however, no case adnexal abscess caused by has reported in the English literature. We herein report ovarian cinaedi. A 38-year-old nulligravid Japanese woman was admitted to our hospital with an abscess. Clinical findings included fever, leukocytosis, and elevated C-reactive protein. Laparoscopic right partial oophorectomy abdominal lavage performed. isolated...
7317 Background: Combination chemotherapy of irinotecan and amrubicin for advanced non-small-cell lung cancer (NSCLC) has not been fully evaluated. To determine the maximum-tolerated dose (MTD), a Phase I study in patients with NSCLC was conducted. Methods: Patients stage IIIB/IV were enrolled this study. Both without prior also eligible. Drugs administered on days 1 8, every 3 weeks. The starting doses 60 35 mg/m2, respectively. Toxicities graded according to National Cancer Institute...
Abstract Background: EGFR inhibitors are effective clinical therapies for mutant NSCLC, but efficacy is limited by the development of acquired drug resistance. The mechanisms resistance include secondary mutations in (T790M) and activation compensatory signaling pathways (MET, IGFR AXL). Mutant selective (WZ4002, CO-1686 AZD9291) preclinical models T790M. Our lab has demonstrated that reactivation ERK a mechanism to WZ4002 (WZ) which could be reversed or prevented using combination WZ MEK...
Abstract Introduction: Non-small cell lung cancers harboring sensitizing gain-of-function mutations in the epidermal growth factor receptor (EGFR) are treated with small molecule EGFR kinase inhibitors including erlotinib and osimertinib. Unfortunately, clinical efficacy of these is limited by progression to drug resistance. Genomic amplification hepatocyte (MET) a prevalent mechanism resistance inhibitors. mutant MET co-dependent on signaling through kinases, whereby either oncogene can...
7189 Background: Gefitinib is an orally active epidermal growth factor receptor tyrosine kinase inhibitor. The introduction of gefitinib had a great clinical impact in the treatment advanced and chemotherapy-refractory non-small cell lung cancer (NSCLC). Although short-term adverse events such as skin rash, hepatotoxicity, interstitial disease have been identified, long-term not clearly elucidated. Method: We retrospectively reviewed 108 cases NSCLC treated with between November 2001...